In mice, a treatment for lung cancer

For mice, the Goliath of lung cancer has a vanquisher in the form of a tiny David.

In a study published in the November issue of Cancer Research, Yale biology researchers Frank J. Slack and Andrea Kasinski revealed that short strands of microRNA, non-coding RNA inhibiting protein translation, were successful in both preventing and curing lung adenocarcinoma in mice. The research is the first to propose that, in a clinical trial using mice, microRNA can be used as a therapeutic to suppress the activation and expression of oncogenic, or cancer-causing, proteins.

“I think this is incredibly promising,” said Roy Herbst, chief of medical oncology at the Yale School of Medicine, who did not participate in the research. Lung cancer, one of the most aggressive cancers, was previously deemed incurable, he said. However, Slack and Kasinski were able to prevent further growth of these tumors in mice subjects.

“The tumors just melted away,” Herbst said.

In preparing the study, the researchers induced lung cancer in mice caused by mutations in the genes KRAS and p53. The p53 gene is mutated in over 50 percent of all cancers and serves as a “springboard” for cancer aggravation, Kasinski said. Ordinarily, wild-type, or unmutated, p53 acts as a tumor suppressor by “turning on” certain genes in its signaling pathway. In this pathway lies miR-34, a microRNA molecule that inhibits the growth of oncogenes. Mutated p53, however, causes miR-34 to be expressed in lower quantities, resulting in these oncogenes’ uncontrolled division. Kasinski and Slack hoped to demonstrate that delivering miR-34 directly to their subjects’ infected lung tissue would prevent this division by restoring part of p53 activity, Kasinski said.

Slack and Kasinski said their research included two studies conducted on the effects of miR-34. In both, miR-34 was delivered to cancerous cells using a virus. During the first study, miR-34 was delivered to the mice at the same time the researchers initiated the lung cancer. Although they are still unsure of what miR-34 does on a molecular level, the research team concluded that the therapy prevented the cancer from forming.

In the second test, the cancer was initiated first and allowed to develop for 10 weeks before the miR-34 was delivered. When the miR-34 was delivered, the tumor stopped growing, Kasinski said. The miR-34 turned part of the p53 pathway back on, presumably enough to prevent the lung cancer from either occurring or further developing.

“I was surprised that we saw such a dramatic effect,” Slack said. “When we showed the result to lung oncologists, they were amazed … We were able to prevent the tumors from forming.”

Research on the regulatory nature of microRNA is relatively new, and its role as a regulatory nature dates back only 12 years, Slack said. He added that more research needs to be done to determine if other microRNA molecules are better for cancer prevention.

The next step for Slack and Kasinski will be to conduct a clinical study in humans. First, however, the team will need to devise an alternate method of delivery for miR-34. Virus delivery, while successful in mice, has been shown to be unsafe in people. The team is currently experimenting with different nanoparticles that will be able to safely transmit miR-34 through the bloodstream.

“We haven’t seen any side effects yet,” Slack said. “[The mice] don’t seem to mind the delivery, and we’re hoping this will also be safe in humans.”

MicroRNA — in particular, miR-34, which has been present in human evolution for 800 billion years — are molecules to which the body has learned how to adapt, he added. The body, therefore, more readily accepts therapies involving the delivery of extra microRNA.

Although the miR-34 treatment was only tested in mice, the researchers are optimistic that the treatment will translate to humans.

“It truly is a very important finding and one that brings great hope for the future treatment of lung cancer,” Herbst said.

Funding for the research was obtained from both the American Cancer Society and the National Institute of Health.